WO2002002541A2 - Inhibiteur d'amine oxydases contenant du cuivre - Google Patents

Inhibiteur d'amine oxydases contenant du cuivre Download PDF

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WO2002002541A2
WO2002002541A2 PCT/FI2001/000637 FI0100637W WO0202541A2 WO 2002002541 A2 WO2002002541 A2 WO 2002002541A2 FI 0100637 W FI0100637 W FI 0100637W WO 0202541 A2 WO0202541 A2 WO 0202541A2
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alkyl
optionally substituted
heterocyclic ring
taken together
hydrogen
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PCT/FI2001/000637
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WO2002002541A3 (fr
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David John Smith
Markku Jalkanen
Ferenc FÜLÖP
László LÁZÁR
Zsolt Szakonyi
Gábor BERNÁTH
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Biotie Therapies Corp.
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Priority to PL36035301A priority Critical patent/PL360353A1/xx
Priority to JP2002507795A priority patent/JP2004502682A/ja
Priority to CA002414799A priority patent/CA2414799A1/fr
Priority to IL15376701A priority patent/IL153767A0/xx
Priority to NZ523463A priority patent/NZ523463A/en
Priority to AU2001282162A priority patent/AU2001282162A1/en
Priority to HU0301625A priority patent/HUP0301625A3/hu
Priority to EP01960763A priority patent/EP1301495A2/fr
Publication of WO2002002541A2 publication Critical patent/WO2002002541A2/fr
Publication of WO2002002541A3 publication Critical patent/WO2002002541A3/fr
Priority to NO20026282A priority patent/NO20026282L/no

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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/13—Amines
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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Definitions

  • the present invention is in the field of medicinal chemistry and is directed to 1,3,4-oxadiazine compounds and their use as inhibitors of copper-containing amine oxidases (E.C. 1.4.3.6) and enzymes of significant identity thereto.
  • the compounds of the present invention have therapeutic utility as drugs to treat diseases including but not limited to a number of inflammatory conditions and diseases (in particular chronic inflammatory conditions or diseases such as chronic arthritis, inflammatory bowel diseases, and chronic skin dermatoses) as well as diseases related to carbohydrate metabolism and to aberrations in adipocyte differentiation or function and smooth muscle cell function.
  • NAP-1 is a human endothelial cell adhesion molecule that has several unique properties that distinguish it from the other inflammation-related adhesion molecules and these are described as follows. NAP-1 has a unique and restricted expression pattern and mediates lymphocyte binding to vascular endothelium
  • NAP-1 is rapidly translocated onto vascular endothelium at sites of inflammation.
  • NAP-1 has a catalytic extracellular domain with a monoamine oxidase activity (Smith, D.J., etal, J. Exp. Med. 188:17-27 (1998)).
  • the cloning and sequencing of the human NAP-1 cD ⁇ A revealed that it encodes a transmembrane protein with homology to a class of enzymes called the copper-containing amine oxidases (E.G. 1.4.3.6).
  • Enzyme assays have shown that VAP-1 possesses a monoamine oxidase (MAO) activity which is present in the extracellular domain of the protein (Smith, D.J., et al, J. Exp. Med. 188:11-21 (1998)).
  • MAO monoamine oxidase
  • NAP-1 is an ecto-enzyme.
  • Analysis of the NAP-1 MAO activity showed that NAP-1 belongs to the class of membrane-bound MAO's termed semicarbazide-sensitive amine oxidases (SSAO). These are distinguished from the widely distributed mitochondrial MAO-A and B flavoproteins by amino acid sequence, cofactor, substrate specificity and sensitivity to certain inhibitors. However, certain substrates and inhibitors are common to both SSAO and MAO activities.
  • the mammalian S SAO' s can metabolize various monoamines produced endogenously or absorbed as dietary or xenobiotic substances.
  • NAP-1 located on the vascular endothelial cell surface can act on circulating primary monoamines with the following reaction pathway.
  • H 2 O 2 is a known signalling molecule that can upregulate other adhesion molecules and this increased adhesion molecule expression may lead to enhanced leukocyte trafficking into areas in which NAP-1 is expressed.
  • 1,3,4-oxadiazines may exist in tautomeric hydrazone form. See, for example, Potekhin, A.A., and Zaitsev, B.D., Khim. Geterotsikl. Soedin. 7( ⁇ :301-308 (1971), and Ioffe, B.V., and Potekin, A.A., Tetrahedron Lett. (36)3505-3508 (1967).
  • V-alkylaminoephedrines including N- (isopropylideneamino)-ephedrine (or R,£-(+)-(2-hydroxy-l-methyl-2- phenylethyl)methylhydrazone-2-propanone):
  • hydrazone compounds were synthesized to evaluate their effect on the bronchial musculature and were found not to exhibit any significant activity. No mention of a 1,3,4-oxadiazine corresponding to the reported hydrazone appears in this reference.
  • NAP-1 SSAO inhibitors that modulate NAP-1 activity would be useful for the treatment of chronic inflammatory conditions or diseases such as chronic arthritis, inflammatory bowel diseases, and chronic skin dermatoses, as well as diseases related to carbohydrate metabolism (including diabetes and complications from diabetes), to aberrations in adipocyte differentiation or function and smooth muscle cell function (in particular, athersclerosis), and to various vascular diseases.
  • the present invention is broadly directed to the use of 1,3,4-oxadiazine compounds of Formula I as inhibitors of the class of copper-containing amine oxidases known as semicarbazide-sensitive amine oxidases (SSAO), including the human SSAO known as Vascular Adhesion Protein-1 (NAP-1).
  • SSAO semicarbazide-sensitive amine oxidases
  • NAP-1 Vascular Adhesion Protein-1
  • compounds of the present invention can function to prevent leukocyte adhesion events mediated through SSAO activity.
  • Compounds of the present invention are therefore useful for treating a number of inflammatory conditions and diseases of connective tissue, skin, and the gastrointestinal, central nervous system, and pulmonary systems, including such conditions as chronic arthritis, inflammatory bowel diseases, and chronic dermatoses.
  • the compounds are also useful for treating diseases related to carbohydrate metabolism (such as diabetes), to aberrations in adipocyte differentiation or function or smooth muscle cell function (such as atherosclerosis and obesity), and to various vascular diseases (such as atheromatous and nonatheromatous ateriosclerosis, ischemic heart disease, and peripheral aterial occlusion).
  • a further aspect of the present invention is to provide a pharmaceutical composition useful for treating disorders responsive to a decrease in SSAO activity, containing an effective amount of a compound of Formula Im ' a mixture with one or more pharmaceutically acceptable carriers or diluents.
  • Another embodiment of the present invention is directed to methods for making compounds of Formula J.
  • One aspect of the invention is to use a specific group of 1,3,4- oxadiazine compounds having the general formula J as defined below, for the manufacture of a pharmaceutical preparation for inhibiting a copper-containing amine oxidase.
  • Another aspect of the invention is to use a specific group of 1,3,4- oxadiazine compounds having the general formula J as defined below, for the manufacture of a pharmaceutical preparation for the treatment of an inflammatory disease or condition, a disease related to carbohydrate metabolism, a disease related to aberrations in adipocyte differentiation or function or smooth muscle cell function, or a vascular disease.
  • a further aspect of the present invention is directed to a method of inhibiting a copper-containing amine oxidase, contacting said amine oxidase with an inhibitory effective amount of a 1,3,4-oxadiazine compound of Formula J:
  • R 1 is hydrogen or Ci-C alkyl
  • R 2 is hydrogen, C ⁇ -C 4 alkyl, C 2 -C alkenyl, aralkyl, C 2 -C ⁇ alkanoyl, C 3 -C ⁇ alkenoyl, C 7 -Cn or aroyl, which is optionally substituted;
  • R 3 , R 4 , R 5 , and R 6 which can be the same or different, are hydrogen, C ⁇ -C alkyl or optionally substituted aryl; or any two of said substituents R 3 , R 4 , R 5 , and R 6 are taken together with the carbon atoms to which they are attached to form an optionally substituted carbocyclic or hetercyclic ring; or R 2 and R 3 are taken together with the atoms to which they are attached to form an optionally substituted heterocyclic ring; and R 7 is hydrogen, C ⁇ -C 4 alkyl, aryl, substituted aryl, heteroaryl, or aralkyl;
  • R 8 is C ⁇ -C alkyl, aryl, substituted aryl, heteroaryl, or aralkyl or 7 andR 8 are taken together with the carbon atoms to which they are attached to form an optionally substituted 5-12 membered carbocyclic or heterocyclic ring.
  • said contacting occurs in vitro. In another embodiment said contacting occurs in vivo.
  • the present invention is directed to methods of treating or preventing inflammatory diseases or conditions using a 1,3,4-oxadiazine of Formula/:
  • R 1 is hydrogen or CrC 4 alkyl
  • R 2 is hydrogen, C 1 -C 4 alkyl, C 2 -C alkenyl, aralkyl, C 2 -C ⁇ alkanoyl, C 3 -C6 alkenoyl, or C 7 -C ⁇ aroyl, which is optionally substituted;
  • R 3 , R 4 , R 5 , and R 6 which can be the same or different, are hydrogen, C ⁇ -C 4 alkyl or optionally substituted aryl; or any two of said substituents R 3 , R 4 , R 5 , and R 6 are taken together with the carbon atoms to which they are attached to form an optionally substituted carbocyclic or heterocyclic ring; or R 2 and R 3 are taken together with the atoms to which they are attached to form an optionally substituted carbocyclic or heterocyclic ring; and
  • R 7 is hydrogen, C C alkyl, aryl, substituted aryl, heteroaryl, or aralkyl
  • R 8 is C C 4 alkyl, aryl, substituted aryl, heteroaryl, or aralkyl
  • R 7 and R 8 are taken together with the carbon atom to which they are attached to form an optionally substituted 5-12 membered carbocyclic or heterocyclic ring.
  • the compounds can be used to treat such conditions or diseases as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and osteoarthritis.
  • the 1,3,4-oxadiazine compounds ofFormula/are used to treat or prevent gastrointestinal inflammatory conditions and diseases, in particular those such as Crohn's disease, ulcerative colitis, and irritable bowel syndrome.
  • the 1,3,4-oxadiazine compounds of Formula/ are used to treat central nervous system inflammatory conditions and diseases, including multiple sclerosis, Alzheimer's disease, and ischaemia-reperfusion injury associated with ischemic stroke.
  • the compounds can be used to treat or prevent such conditions or diseases as asthma and adult respiratory distress syndrome.
  • the 1,3,4-oxadiazine compounds ofFor ula/ are used to treat or prevent diseases related to carbohydrate metabolism and complications thereof, such as diabetes and complications from diabetes, microvascular and macrovascular diseases such as atherosclerosis, vascular retinopathies, and neuropathies such as polyneuropathy, mononeuropathies, and autonomic neuropathy.
  • diseases related to carbohydrate metabolism and complications thereof such as diabetes and complications from diabetes, microvascular and macrovascular diseases such as atherosclerosis, vascular retinopathies, and neuropathies such as polyneuropathy, mononeuropathies, and autonomic neuropathy.
  • 1,3,4-oxadiazine compounds ofFormula/ are used to treat or prevent diseases related to or caused by aberrations in adipocyte differentiation or function, such as atherosclerosis or obesity.
  • vascular diseases such as atheromatous and nonatheromatous arteriosclerosis, ischemic heart disease, and Raynaud's Disease and Phenomenon.
  • Another aspect of the present invention is directed to novel compounds of Formula/, as well as tautomers, or pharmaceutically acceptable solvates, hydrates, or salts thereof, as described above; provided that R 3 and R 4 are not hydrogen or CrC 4 alkyl when R 7 and/or R 8 are CrC 4 alkyl or optionally substituted phenyl, or when R 7 and R 8 are taken together with the carbon atom to which they are attached for form an unsubstituted C5-G7 cycloalkyl group.
  • the present invention is also directed to pharmaceutical compositions of these novel compounds ofFormula /, as well as to methods of making the novel compounds.
  • Preferred compounds are those of Formula/ wherein R 1 is hydrogen or C1-C4 alkyl, preferably hydrogen; and R 2 is hydrogen, C1-C4 alkyl, C 2 -C 4 alkenyl, C6-C10 ar(C ⁇ -C 4 )alkyl, C 2 -C ⁇ alkanoyl, C2-C6 alkenoyl, or benzoyl, any of which may be optionally substituted, and R 2 is preferably Ci-C 4 alkyl or optionally substituted benzyl.
  • Preferred substituents for the benzyl group of R 2 are lower alkyl, especially methyl, and nitro, methoxy and halogen, especially chlorine.
  • substituted benzyl groups are ?-toluyl, p- mtrobenzyl, -methoxybenzyl, and ⁇ -chlorobenzyl.
  • Suitable values of R 1 are hydrogen, methyl, ethyl, w-propyl, i-propyl, w-butyl, /-butyl, and t-butyl.
  • Suitable values of R 2 include hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, acetyl, benzoyl, p-toluyl, ?-nitrobenzyl, 7-methoxybenzyl, and -chlorobenzyl.
  • Preferred compounds ofFormula / also include those compounds wherein R 3 , R 4 , R 5 and R 6 , which can be the same or different, are hydrogen, optionally substituted C ⁇ -C 4 alkyl, or optionally substituted phenyl.
  • Preferred substituents for R 3 , R 4 , R 5 and R 6 are hydrogen and optionally substituted phenyl.
  • Preferred substituted phenyl groups are those substituted with a lower alkyl, especially methyl, or a halogen such as chlorine or fluorine.
  • Especially preferred substituted phenyl groups include o-tolyl, w-tolyl, -tolyl, ⁇ -fluorophenyl and -chlorophenyl.
  • Another group of preferred compounds ofFormula / are those wherein two of said substituents R 3 , R 4 , R 5 and R 6 are taken together to form an optionally substituted 5-12 membered carbocyclic or heterocyclic ring.
  • the ring formed by two of the substituents R 3 , R 4 , R 5 and R 6 and the carbon atoms to which they are attached is preferably a 5 to 7 membered single ring or a ring to which further rings are condensed ⁇ i.e., a ring system).
  • Said 5 to 7 membered ring can be either cis or trans condensed to the oxadiazine ring, and either spiro or fused.
  • the ring can be heterocyclic or carbocyclic and said ring can be saturated or comprise double bonds.
  • the ring or ring system can be unsubstituted or substituted, wherein the substituent can be alkyl, preferably methyl.
  • the ring is a saturated carbocyclic ring.
  • Suitable rings include cyclopentane, cyclohexane, 4-methyl-cyclohexane, cycloheptane or a ring included in the adamantane ring system.
  • Another group of preferred compounds are those of Formula/in whichR 2 and R 3 are taken together to form an optionally substituted heterocyclic ring.
  • the heterocyclic ring formed by the substituents R 2 and R 3 is a 5 to 6 membered nitrogen containing saturated ring.
  • Said ring can be unsubstituted or substituted.
  • the substituent is alkyl.
  • this 5 to 6 membered nitrogen containing ring can be condensed another ring to form a 1,2,3,4- tetrahydroquinoline, 1,2,3,4,-tetrahydroisoquinoline or 2,3-dihydroindole structure.
  • piperidine 1,2,3,4-tetrahydroisoquinoline and 6,7-dimethoxy-l,2,3,4-tetrahydro-isoquinoline.
  • R 4 is hydrogen
  • Preferred compounds also include those ofFormula /in which R 7 and R 8 , which can be the same or different, are C ⁇ -C alkyl, or C ⁇ -Cio a ⁇ d-G ⁇ alkyl. Preferred values of R 7 and R 8 include C ⁇ -C 4 alkyl, especially methyl and ethyl.
  • R 7 and R 8 are taken together with the carbon atoms to which they are attached to form an optionally substituted 5-12 membered carbocyclic or heterocyclic ring.
  • the 5-12 membered ring can be saturated or unsaturated carbocyclic or heterocyclic and said ring can be unsubstituted or substituted.
  • the substituent can be alkyl, aralkyl, or substituted aralkyl.
  • An especially preferred substituent is benzyl.
  • Saturated rings are preferable.
  • a particularly preferable spiro-condensed ring is N- benzylpiperidine.
  • a preferred subgenus of compounds has Formula la:
  • R 12 is hydrogen, C ⁇ -C 4 alkyl or phenyl(C ⁇ -C 3 )alkyl
  • R 13 is hydrogen, C ⁇ -C 4 alkyl or phenyl; or R 15 is hydrogen or C C alkyl;
  • R 13 and R 15 are taken together with the carbon atoms to which they are attached to form a five to seven membered cycloalkyl ring;
  • R 14 and R 16 are independently hydrogen or C ⁇ -C alkyl
  • R 17 is C C 4 alkyl
  • R 18 is C x -C 4 alkyl, or R 17 and R 18 are taken together with the carbon atom to which they are attached to form a five or six membered saturated ring optionally including one ring nitrogen (NR 19 ) where R 19 is hydrogen, CrC alkyl or phenyl(Ci-C 3 )alkyl.
  • R 22 is hydrogen, C ⁇ -C 4 alkyl or benzyl, preferably methyl or benzyl;
  • R 23 is hydrogen or C 1 -C 4 alkyl, preferably hydrogen or methyl
  • R 24 is hydrogen or C 1 -C alkyl
  • R 25 is hydrogen, Ci-C 4 alkyl or phenyl, preferably hydrogen or phenyl;
  • R 26 is hydrogen or C 1 -C alkyl
  • R R 2"7 is C ⁇ -C 4 alkyl
  • R 28 is Ci-C 4 alkyl; and X is a covalent bond, -CH 2 - or -NR 19 -, where R 19 is hydrogen, C1-C4 alkyl or benzyl.
  • Examples of compounds of, and useful in, the present invention include: 9-benzyl-2-methyl-5-oxa-l,2,9-triazaspiro[5.5]undecane;
  • alkyl refers to both straight and branched chain radicals of up to 12 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl.
  • C ⁇ -C alkyl is a straight or branched alkyl and thus can include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and isobutyl.
  • alkenyl is used herein to mean a straight or branched chain radical of 2-20 carbon atoms, unless the chain length is limited thereto, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1- butenyl, 2-butenyl, and the like.
  • the alkenyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms in length most preferably from 2 to 4 carbon atoms in length.
  • aryl as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 12 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl.
  • aralkyl as employed herein should be interpreted as any aryl attached to the alkyl, which is a chain of 1 to 6 carbon atoms and which in turn can be straight or branched. Preferably, the chain contains 1 to 3 carbon atoms.
  • a preferred aryl group is phenyl, which can be substituted or unsubstituted.
  • Preferable substituents are lower alkyl (i.e., Ci-C alkyl), especially methyl, or a halogen.
  • alkanoyl refers to a carbonyl moiety to which is attached any of the above alkyl groups.
  • C 2 -C ⁇ alkanoyl includes, but is not limited to, ethanoyl, propanoyl, butanoyl, 2-methyl- propanoyl, pentanoyl, hexanoyl.
  • alkenoyl is used herein to mean a carbonyl moiety to which is attached any of the above alkenyl groups.
  • C 2 -C6 alkenoyl refers to, but is not limited to, ethenoyl, 1-propenoyl, 2-propenoyl, 2-methyl-l- propenoyl, 1-butenoyl, 2-butenoyl, and the like.
  • the alkenyl chain is 2 to 10 carbon atoms in length, and more preferably, 2 to 6 carbon atoms in length.
  • carrier ring refers to a monocyclic or bicyclic aromatic ring or ring system containing from 6 to 12 carbons in the ring portion, as defined above, or to any 3- to 9-membered mono- or 7- to 10-membered bicyclic carbon ring system, any ring of which may be saturated or unsaturated.
  • Typical examples include phenyl, naphthyl, and cyclohexyl.
  • heterocyclic ring represents a stable 5- to 7- membered mono- or bicyclic or stable 7- to 12-membered bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • rings containing one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms are especially useful.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic groups include piperidinyl, piperazinyl, N-benzylpiperidine, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinucli
  • heteroaryl refers to groups having 5 to 14 ring atoms; 6, 10 or 14 B electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms (where examples of heteroaryl groups are: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H
  • halogen or "halo" as employed herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine, with chlorine being preferred.
  • substituted refers to one or more groups independently selected from the group consisting of halo, halo (Cj.
  • Preferred optional substituents include: halo, ar(C ⁇ -6)alkyl, aryl, and C ⁇ -6 alkyl.
  • cycloalkyl as employed herein by itself or as part of another group refers to cycloalkyl groups containing 3 to 9 carbon atoms. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl.
  • hydroxyalkyl refers to any of the above alkyl groups substituted by one or more hydroxyl moieties.
  • carboxyalkyl refers to any of the above alkyl groups substituted by one or more carboxylic acid moieties.
  • haloalkyl refers to any of the above alkyl groups substituted by one or more chlorine, bromine, fluorine or iodine with fluorine and chlorine being preferred, such as chloromethyl, iodomethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and 2-chloroethyl.
  • haloalkoxy refers to any of the above haloalkyl groups bonded to an oxygen atom, such as trifluromethoxy, trichloromethoxy, and the like.
  • alkoxy is used herein to mean a straight or branched chain radical of 1 to 20 carbon atoms, unless the chain length is limited thereto, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, «-propoxy, isopropoxy, and the like.
  • the alkoxy chain is 1 to 10 carbon atoms in length, more preferably 1 to 8 carbon atoms in length.
  • Some of the compounds disclosed herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms.
  • the present invention is also meant to encompass racemic mixtures, resolved forms and mixtures thereof, as well as the individual enantiomers that may be separated according to methods that are well know to those of ordinary skill in the art.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended to include both E and Z geometric isomers.
  • stereoisomers is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).
  • asymmetric center or “chiral center” refers to a carbon atom to which four different groups are attached.
  • enantiomer or “enantiomeric” refers to a molecule that is nonsuperimposeable on its mirror image and hence optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction.
  • racemic refers to a mixture of equal parts of enantiomers and which is optically inactive.
  • resolution refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.
  • enantiomeric excess refers to a mixture wherein one enantiomer is present is a greater concentration than its mirror image molecule.
  • Another aspect of the present invention is directed to methods for preparing compounds ofFormula /.
  • the compounds of the present invention can be prepared by one of the following routes. Synthesis of the compounds of Formula / (compounds ) starts from hydrazino alcohols II and uses ketones IV or ketone equivalents, e.g. acetals V (R 9 is preferably a methyl or ethyl group), as condensing agents.
  • Condensations are performed at 20-120 °C, with or without acidic or basic catalysts, or adsorbents of water.
  • acidic or basic catalysts or adsorbents of water.
  • acidic catalysts are hydrochloric, /?-toluenesulfonic, acetic, and tartaric and oxalic acids.
  • An “acidic catalyst” may also include any strongly acid resin ion-exchange resin suitable for non-aqueous catalysis, such as Amberlist ® 15.
  • An illustrative example of "a basic catalyst” is triethylamine.
  • water adsorbent includes dried magnesium sulfate, silica and molecular sieve 4A.
  • Hydrazino alcohols TL are known from the literature or can be prepared following the literature processes by starting from amino alcohol precursors HI (Taguchi, T. et al, J. Org. Chem. 29: 1097-1103 (1964); Takahashi, H, et al, Chem. Pharm. Bull. 39:836-842 (1991); Shen, J.K., etal, J. Chem. Soc, Perkin Trans. 7:2087-2097 (1993); Rosling, A, etal, Heterocycles 45:95-106 (1997); Rosling, A., et al, J. Chem. Res.(S):492 (1998); J Chem. Res. (M):2231 -2250 (1998)).
  • hydrazino alcohols ⁇ are used as single diastereomers.
  • the synthesis of the enantiomers of compounds I starts from enantiomerically pure hydrazino alcohols ⁇ , which are known from the literature or can be prepared following the literature processes (Trepanier, D.L., et al, J. Org. Chem. 29:668-672 (1964)). Condensations occur without racemization. Enantiomerically pure products I can also be prepared by standard enantiomer separation techniques from the racemates of I.
  • the compounds of this invention are useful in the form of acid addition salts.
  • pharmaceutically acceptable acid addition salt is intended to apply to any non-toxic organic and inorganic acid addition salts of the base compounds ofFormula /.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids.
  • Illustrative organic acids which form suitable salts include acetic, lactic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids
  • the present invention provides a method of treating VAP-1 mediated conditions by selectively inhibiting VAP-1 SSAO activity, which method comprises administering to an animal in need thereof a therapeutically effective amount of a compound selected from the class of compounds depicted by Formula /, wherein one or more compounds of Formula /is administered in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
  • the compounds of the present invention can be used to treat inflammatory conditions and diseases including but not limited to connective tissue inflammatory conditions and diseases such as ankylosing spondylitis, Reiter's syndrome, psoriatic arthritis, osteoarthritis or degenerative joint disease, rheumatoid arthritis, Sjogren's syndrome, Behcet's syndrome, relapsing polychondritis, systemic lupus erythematosus, discoid lupus erythematosus, systemic sclerosis, eosinophilic fasciitis, polymyositis and dermatomyositis, polymyalgia rheumatica, vasculitis, temporal arteritis, polyarteritis nodosa, Wegener's granulomatosis, mixed connective tissue disease, and juvenile rheumatoid arthritis; gastrointestinal inflammatory conditions and diseases such as Crohn's disease, ulcerative colitis, irritable bowel syndrome
  • the compounds of the invention can be used to treat diseases related to carbohydrate metabolism and complications thereof, such as diabetes and complications of diabetes including, but not limited to microvascular and macrovascular disease such as atherosclerosis, vascular retinopathies, retinopathy, nephropathy and nephrotic syndrome, neuropathies such as polyneuropathy, mononeuropathies, and autonomic neuropathy, and foot ulcers and joint problems, as well as increased risk of infection; diseases related to or caused by aberrations in adipocyte differentiation or function such as atherosclerosis and obesity; and vascular diseases such as atheromatous and nonatheromatous ateriosclerosis, ischemic heart disease including myocardial infarction, peripheral aterial occlusion, thromboangiitis obliterans (Buerger's disease), and Raynaud's disease and phenomenon.
  • microvascular and macrovascular disease such as atherosclerosis, vascular retinopathies, retinopathy, nephropathy and nephrotic syndrome
  • the present compounds can be used to treat atherosclerosis. It is known that VAP-1 is expressed on adipocytes, smooth muscle cells, endothelial cells and is related to inflammation. Atherosclerotic plaque consists of accumulated intracellular and extracellular lipids, smooth muscle cells, connective tissue, and glycosaminoglycans. The earliest detectable lesion of atherosclerosis is the fatty streak (consisting of lipid-laden foam cells, which are macrophages that have migrated as monocytes from the circulation into the subendothelial layer of the intima), which later evolves into the fibrous plaque (consisting of intimal smooth muscle cells surrounded by connective tissue and intracellular and extracellular lipids).
  • treat inflammation is intended to include the administration of compounds of the present invention to a subject for purposes, which can include prophylaxis, amelioration, prevention or cure of an inflammatory condition or disease. Such treatment need not necessarily completely ameliorate the inflammatory condition or disease. Further, such treatment can be used in conunction with other traditional treatments for reducing the inflammatory condition known to those of skill in the art.
  • the compounds of the present invention may be administered in an effective amount within the dosage range of about 0.1 ⁇ g kg to about 300 mg/kg, preferably between 1.0 ⁇ g/kg to 10 mg/kg body weight.
  • Compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • compositions of the present invention can be administered to any animal that can experience the beneficial effects of the compounds of the invention.
  • animals Foremost among such animals are humans, although the invention is not intended to be so limited.
  • compositions of the present invention can be administered by any means that achieve their intended purpose.
  • administration can be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, or intradermal injections, or by transdermal, buccal, or ocular routes.
  • administration can be by the oral route.
  • Particularly preferred is oral administration.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • the pharmaceutical preparations of the compounds can contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
  • compositions of the present invention are manufactured in a manner that is, itself, known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
  • pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
  • fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth,
  • disintegrating agents can be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Auxiliaries are, above all, flow-regulating agents and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings, that, if desired, are resistant to gastric juices.
  • concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, are used.
  • Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
  • Other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
  • the push-fit capsules can contain the active compounds in the form of granules that may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are preferably dissolved or suspended in suitable liquids such as fatty oils or liquid paraffin.
  • stabilizers may be added.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example water- soluble salts and alkaline solutions.
  • alkaline salts are ammonium salts prepared, for example, with Tris, choline hydroxide, bis-Tris propane, N-methylglucamine, or arginine.
  • suspensions of the active compounds as appropriate oily injection suspensions can be administered.
  • Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400).
  • Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, for example sodium carboxymethyl cellulose, sorbitol, and/or dextran.
  • the suspension may also contain stabilizers.
  • the title compound was synthesized using each of the following three synthetic methods.
  • the title compound was synthesized using each of the following two synthetic methods.
  • Method 2b To a solution of 2-(N / -methylhydrazino)-l-phenylethanol (0.50 g, 3 mmol) in dry toluene (25 ml), l-benzylpiperidin-4-one (0.57 g, 3 mmol) and a catalytic amount (1 drop) of triethylamine were added. The reaction mixture was left to stand at room temperature for 24 hours and then evaporated to dryness. Evaporation was repeated after the addition of dry toluene (10 ml).
  • the title compound was synthesized using each of the following two synthetic methods.
  • Method 3b To a solution of (lR,2S)-N ⁇ -aminoephedrine (0.30 g, 1.7 mmol) in dry benzene (30 ml), l-benzylpiperidin-4-one (0.31 g, 1.6 mmol) was added, followed by a few drops of ethanol containing 22% hydrogen chloride. The reaction mixture was stirred at room temperature for 6 hours, and then evaporated to dryness. The residue was dissolved in 5 ml ethanol containing 22% hydrogen chloride, after a few minutes the solution was evaporated to dryness and the residue was crystallized from an ethanol/diethyl ether mixture. 13 C-NMR: see Method 3 a.
  • the title compound was synthesized using each of the following four synthetic methods.
  • Method 4b To a solution of (lS,2R)-7V-aminoephedrine (0.30 g, 1.7 mmol) in dry benzene (40 ml) cyclohexanone (0.83 g, 8.5 mmol) and a catalytic amount (some crystals) of 7-toluenesulfomc acid were added. The reaction mixture was left to stand at room temperature for 6 hours, and then evaporated to dryness. The residue was dissolved in 5 ml ethanol containing 22% hydrogen chloride, after a few minutes the solution was evaporated to dryness and the semisolid residue was crystallized from an ethanol/diethyl ether mixture. 13 C- NMR: see Method 4a.
  • Method 4c To a solution of (lS,2R)-iV-aminoephedrine (0.30 g, 1.7 mmol) in dry benzene (40 ml), cyclohexanone (0.83 g, 8.5 mmol) and Amberlist ® 15 ion-exchange resin (0.1 g) were added. The reaction mixture was stirred at room temperature for 5 hours, the ion-exchange resin was then filtered off and the filtrate was evaporated to dryness. The residue was dissolved in 5 ml ethanol containing 22% hydrogen chloride, after a few minutes the solution was evaporated to dryness and the semisolid residue was crystallized from an ethanol/diethyl ether mixture. 13 C-NMR: see Method 4a.
  • Method 4d To a solution of (lS,2R)-N-aminoephedrine (0.30 g, 1.7 mmol) in dry methylene chloride (25 ml), cyclohexanone (0.83 g, 8.5 mmol) and anhydrous magnesium sulfate (5 g) were added. The reaction mixture was stirred at room temperature for 10 hours, the magnesium sulfate was then filtered off and the filtrate was evaporated to dryness. The residue was dissolved in 5 ml ethanol containing 22% hydrogen chloride, after a few minutes the solution was evaporated to dryness and the semisolid residue was crystallized from an ethanol/diethyl ether mixture. 13 C-NMR: see Method 4a.
  • the title compound was synthesized using each of the following three synthetic methods.
  • Method 5a To a solution of l-oxa-2-azaspiro[2.5]octane (0.60 g, 5.3 mmol) in diethyl ether (20 ml), a solution of ezs-2-(methylamino)cyclohexanol (0.68 g, 5.3 mmol) in diethyl ether (5 ml) was added. The reaction mixture was stirred at room temperature for 30 minutes and then evaporated to dryness. The residue was dissolved in 5 ml ethanol containing 22% hydrogen chloride, after a few minutes the solution was evaporated to dryness and the semisolid residue was crystallized from an ethanol/diethyl ether mixture. 13 C-NMR (500 MHz, solid state): ⁇ 24.01 (broad), 42.6, 60.1, 65.9, 86.86 (C-2).
  • Method 5b To a solution of cis-2-(JV / -methylhydrazino)cyclohexanol (0.43 g, 3 mmol) in dry benzene (40 ml), cyclohexanone (1.47 g, 15 mmol) and molecular sieve 4A (8 g) were added. The reaction mixture was stirred at room temperature for 10 hours, the molecular sieve was then filtered off and the filtrate was evaporated to dryness. The residue was dissolved in 5 ml ethanol containing 22% hydrogen chloride, after a few minutes the solution was evaporated to dryness and the semisolid residue was crystallized from an ethanol/diethyl ether mixture. 13 C-NMR: see Method 5a.
  • Method 5c To a solution of cz ' 5-2-(N / -methylhydrazino)cyclohexanol (0.43 g, 3 mmol) in dry toluene (40 ml), cyclohexanone (1.47 g, 15 mmol) and silica gel (0.035-0.07 mm, 2 g) were added. The reaction mixture was stirred at room temperature for 8 hours, the silica gel was then filtered off and the filtrate was evaporated to dryness. The residue was dissolved in 5 ml ethanol containing 22%o hydrogen chloride, after a few minutes the solution was evaporated to dryness and the semisolid residue was crystallized from an ethanol/diethyl ether mixture. 13 C-NMR: see Method 5a.
  • Method 6b A solution of a mixture of trans-2-(N l - methylhydrazino)cyclohexanol (0.35 g, 2.4 mmol) in dry acetone (40 ml) and a catalytic amount of ethanol containing 22% hydrogen chloride (1 drop) was left to stand at room temperature for 72 hours. The solution was then evaporated to dryness and the residue was recrystallized from a methanol/diethyl ether mixture. 13 C-NMR: see Method 6a.
  • the title compound was synthesized using each of the following three synthetic methods.
  • Method 8a To a solution of 2-amino-l,2,3,4-tetrahydroisoquinoline 3- methanol (0.53 g, 3 mmol) in 2,2-dimethoxypropane (25 ml), a catalytic amount of p-toluenesulfonic acid was added. The reaction mixture was left to stand at room temperature for 24 hours and then evaporated to dryness. The pale-yellow oily product was dissolved in methanol (2 ml) and was converted to the crystalline dihydrochloride salt by using ethanol containing 22% hydrogen chloride (1 ml) and diethyl ether. The crystals were filtered off and recrystallized from methanol/diethyl ether.
  • Method 8c 2-Amino-l,2,3,4-tetrahydroisoquinoline 3-methanol hydrochloride (0.64 g, 3 mmol) was suspended in dry acetone (40 ml). The reaction mixture was stirred at room temperature for 36 hours and then evaporated to dryness. The semisolid residue crystallized on treatment with methanol/diethyl ether. The crystals were filtered off and recrystallized from metharidl diethyl ether. ⁇ C-NMR: see Method 8a.
  • VAP-1 SSAO activity was measured using the coupled colourimetric method essentially as described for monoamine oxidase and related enzymes (Holt, A., et al, Anal Biochem. 244:314-392 (1997)). Recombinant human VAP-1
  • SSAO expressed in Chinese Hamster Ovary (CHO) cells was used as a source of
  • VAP-1 SSAO for activity measurements.
  • Native CHO cells have negligible SSAO activity. These cells and their culture have previously been described (Smith, D. J., et al. , J. Exp. Med. 188:11-21 (1998)).
  • a cell lysate was prepared by suspending approximately 3.6 x 10 8 cells in 25ml lysis buffer (150mMNaCl, lOmMTris-Base pH 7.2, 1.5 mM MgCl 2 , 1% NP40, 1% Aprotinin, and ImM PMSF) and incubating at 4°C overnight on a rotating table.
  • the lysate was clarified by centrifugation at 21200 g for 30 min at 4°C and the supernatant used directly in the assay.
  • the VAP-1 SSAO assay was performed in 96 well microtitre plates as follows. To each well was added a predetermined amount of inhibitor if required. The amount of inhibitor varied in each assay but was generally at a final concentration of between 10 nM and 2.5 mM. Controls lacked inhibitor. The inhibitor was in a total volume of 20 :1 in water. The following reagents were then added.
  • Human MAO was prepared from human liver by homegenising liver samples 1 :25 (w/v) in ice-cold potassium phosphate buffer (0.2 M, pH 7.6) with a hand held Ten Broeck homogeniser. After centrifugation at 1000 g and 4°C for 15 min the supernatant was carefully withdrawn and used as the source of MAO. Total MAO activity was measured in a similar way as for VAP-1 SSAO except that 2,4-dichlorophenol was replaced by ImM vanillic acid. To each well was added a predetermined amount of inhibitor if required. The amount of inhibitor varied in each assay but was generally at a final concentration of between 10 nM and 2.5 mM. Controls lacked inhibitor.
  • the inhibitor was in a total volume of 20 :1 in water. The following reagents were then added. 0.2 M potassium phosphate buffer pH 7.6 for a total reaction volume of 300 ⁇ l, 50 ⁇ l of freshly made chromogenic solution (as above) and 50 ⁇ l of MAO preparation. The plates were incubated for 30 min at 37°C and the background absorbance measured at 490 nm using a Wallac Victor II multilabel counter. To initiate the enzyme reaction 20 ⁇ l of 5 mM tyramine (final concentration 0.5 mM) was added and the plate incubated for 1 h at 37°C. The increase in absorbance, reflecting MAO activity, was measured at 490nm.

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Abstract

L'invention concerne des composés du type 1,3,4-oxydiazine jouant le rôle d'inhibiteurs d'amine oxydases contenant du cuivre, généralement connues sous le nom d'amine oxydases sensibles au semicarbazide (SSAO), y compris la SSAO humaine connue en tant que protéine-1 d'adhésion vasculaire (VAP-1). Ces inhibiteurs de SSAO peuvent être utilisés, sur le plan thérapeutique, comme médicaments pour traiter des états et des maladies comprenant, de façon non exclusive, un certain nombre d'états et de maladies inflammatoires (en particulier d'états inflammatoires chroniques, telles que l'arthrite chronique, les maladies intestinales inflammatoires et les dermatoses chroniques), les maladies associées au métabolisme des hydrates de carbone et aux aberrations de la différenciation ou de la fonction adipocytaires et de la fonction cellulaire des muscles lisses, et les maladies vasculaires. Lesdits composés correspondent à la formule générale (I), dans laquelle R?1, R2, R3, R4, R5, R6, R7 et R8¿ correspondent à la définition donnée dans la description. L'invention concerne également un tautomère, un isomère, un produit de dégradation alcoolique hydrazino, ou un solvate, hydrate ou sel pharmaceutiquement acceptable de ces composés.
PCT/FI2001/000637 2000-07-05 2001-07-04 Inhibiteur d'amine oxydases contenant du cuivre WO2002002541A2 (fr)

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PL36035301A PL360353A1 (en) 2000-07-05 2001-07-04 Inhibitors of copper-containing amine oxidases
JP2002507795A JP2004502682A (ja) 2000-07-05 2001-07-04 銅含有アミン・オキシダーゼの阻害剤
CA002414799A CA2414799A1 (fr) 2000-07-05 2001-07-04 Inhibiteur d'amine oxydases contenant du cuivre
IL15376701A IL153767A0 (en) 2000-07-05 2001-07-04 Inhibitors of copper-containing amine oxidases
NZ523463A NZ523463A (en) 2000-07-05 2001-07-04 Inhibitors of copper-containing amine oxidases
AU2001282162A AU2001282162A1 (en) 2000-07-05 2001-07-04 Inhibitors of copper-containing amine oxidases
HU0301625A HUP0301625A3 (en) 2000-07-05 2001-07-04 1,3,4-oxadiazine-compounds as inhibitors of copper-containing amine oxidases, process for their preparation and their use for preparation of pharmaceutical compositions
EP01960763A EP1301495A2 (fr) 2000-07-05 2001-07-04 Inhibiteur d'amine oxydases contenant du cuivre
NO20026282A NO20026282L (no) 2000-07-05 2002-12-30 Inhibitorer av kobberholdige aminoksydaser

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004087138A1 (fr) * 2003-03-31 2004-10-14 Sucampo Ag Procede de traitement de maladie vasculaire hyperpermeable
WO2005072738A1 (fr) * 2004-01-30 2005-08-11 Faron Pharmaceuticals Oy Compositions particulierement utiles au traitement ou a la prevention du syndrome metabolique
US7125901B2 (en) 2003-01-27 2006-10-24 Astellas Pharma Inc. Thiazole derivatives
KR20110022574A (ko) 2008-05-30 2011-03-07 가부시키가이샤 아루떼꾸 우에노 벤젠 또는 티오펜 유도체 및 ｖａｐ－１ 억제제로서 이의 용도
WO2011034078A1 (fr) 2009-09-16 2011-03-24 アステラス製薬株式会社 Composé de glycine
US8119651B2 (en) 2004-01-30 2012-02-21 Biotie Therapies Corp. Compositions useful especially for treatment or prevention of metabolic syndrome
WO2012120195A1 (fr) 2011-03-08 2012-09-13 Biotie Therapies Corporation Nouveaux composés de pyridazinone et pyridone
WO2012124696A1 (fr) 2011-03-15 2012-09-20 アステラス製薬株式会社 Composé de guanidine
US8507690B2 (en) 2008-01-31 2013-08-13 R-Tech Ueno, Ltd. Thiazole derivative and use thereof as VAP-1 inhibitor
WO2014199171A1 (fr) 2013-06-12 2014-12-18 Proximagen Limited Nouvelles utilisations thérapeutiques d'inhibiteurs enzymatiques
WO2015159112A1 (fr) 2014-04-15 2015-10-22 Pécsi Tudományegyetem Inhibiteurs d'amine oxydase sensibles au semi-carbazide, destinés à être utilisés comme analgésiques dans une neuropathie traumatique et une inflammation neurogène
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RU2595868C1 (ru) 2015-03-27 2016-08-27 Виктор Вениаминович Тец Лекарственное средство с гепатопротекторной активностью
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US7125901B2 (en) 2003-01-27 2006-10-24 Astellas Pharma Inc. Thiazole derivatives
US7442715B2 (en) 2003-01-27 2008-10-28 Astellas Pharma Inc. Thiazole derivatives
JP4758337B2 (ja) * 2003-03-31 2011-08-24 株式会社アールテック・ウエノ 血管透過性亢進疾患を治療する方法
JP2006522110A (ja) * 2003-03-31 2006-09-28 スキャンポ アーゲー 血管透過性亢進疾患を治療する方法
CN1794988B (zh) * 2003-03-31 2010-07-28 株式会社·R-技术上野 用于治疗血管渗透性过高疾病的组合物
WO2004087138A1 (fr) * 2003-03-31 2004-10-14 Sucampo Ag Procede de traitement de maladie vasculaire hyperpermeable
WO2005072738A1 (fr) * 2004-01-30 2005-08-11 Faron Pharmaceuticals Oy Compositions particulierement utiles au traitement ou a la prevention du syndrome metabolique
EP1708711A1 (fr) † 2004-01-30 2006-10-11 Faron Pharmaceuticals OY Compositions particulierement utiles au traitement ou a la prevention du syndrome metabolique
JP2007519688A (ja) * 2004-01-30 2007-07-19 ファロン ファーマシューティカルズ オサケ ユキチュア メタボリックシンドロームの治療または予防に特に有効な組成物
US8119651B2 (en) 2004-01-30 2012-02-21 Biotie Therapies Corp. Compositions useful especially for treatment or prevention of metabolic syndrome
US8507690B2 (en) 2008-01-31 2013-08-13 R-Tech Ueno, Ltd. Thiazole derivative and use thereof as VAP-1 inhibitor
EP2676955A1 (fr) 2008-01-31 2013-12-25 R-Tech Ueno, Ltd. Dérivé de thiazole et son utilisation en tant qu'inhibiteur VAP-1
US8999989B2 (en) 2008-05-30 2015-04-07 R-Tech Ueno, Ltd. Benzene or thiophene derivative and use thereof as VAP-1 inhibitor
KR20110022574A (ko) 2008-05-30 2011-03-07 가부시키가이샤 아루떼꾸 우에노 벤젠 또는 티오펜 유도체 및 ｖａｐ－１ 억제제로서 이의 용도
EP2886534A1 (fr) 2008-05-30 2015-06-24 R-Tech Ueno, Ltd. Dérivé de benzène ou thiophène et son utilisation en tant qu'inhibiteur VAP-1
US9603833B2 (en) 2008-05-30 2017-03-28 R-Tech Ueno, Ltd. Benzene or thiophene derivative and use thereof as VAP-1 inhibitor
US8802679B2 (en) 2009-09-16 2014-08-12 Astellas Pharma Inc. Glycine compound
WO2011034078A1 (fr) 2009-09-16 2011-03-24 アステラス製薬株式会社 Composé de glycine
WO2012120195A1 (fr) 2011-03-08 2012-09-13 Biotie Therapies Corporation Nouveaux composés de pyridazinone et pyridone
WO2012124696A1 (fr) 2011-03-15 2012-09-20 アステラス製薬株式会社 Composé de guanidine
KR20140014153A (ko) 2011-03-15 2014-02-05 아스테라스 세이야쿠 가부시키가이샤 구아니딘 화합물
US8716470B2 (en) 2011-03-15 2014-05-06 Astellas Pharma Inc. Guanidine compound
EP3002278A1 (fr) 2011-03-15 2016-04-06 Astellas Pharma Inc. Composé de guanidine
US9051283B2 (en) 2011-03-15 2015-06-09 Astellas Pharma Inc. Guanidine compound
US9556160B2 (en) 2011-03-15 2017-01-31 Astellas Pharma Inc. Guanidine compound
WO2014199171A1 (fr) 2013-06-12 2014-12-18 Proximagen Limited Nouvelles utilisations thérapeutiques d'inhibiteurs enzymatiques
WO2015159112A1 (fr) 2014-04-15 2015-10-22 Pécsi Tudományegyetem Inhibiteurs d'amine oxydase sensibles au semi-carbazide, destinés à être utilisés comme analgésiques dans une neuropathie traumatique et une inflammation neurogène
WO2015189534A1 (fr) 2014-06-12 2015-12-17 Proximagen Limited Inhibiteurs de vap-1 pour le traitement de la dystrophie musculaire
WO2016194390A1 (fr) 2015-06-05 2016-12-08 R-Tech Ueno, Ltd. Composition pharmaceutique pour utilisation dans le traitement du cancer
EP3777846A1 (fr) 2015-12-07 2021-02-17 BenevolentAI Cambridge Limited Inhibiteurs de vap-1 for traitmanet de la douleur

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